In the search for nonflammable substitutes for halothane, new fluorinated inhalation anesthetic agents have been developed. Methoxyflurane has been shown to produce dose-related polyuric, vasopressin-resistant nephrotoxicity in man and animals due primarily to its metabolism to inorganic fluoride. More recently, enflurane, isoflurane, synthane, and sevoflurane have been developed. All have been shown to be metabolized to inorganic fluoride, and, therefore, are potential nephrotoxins. We propose to study the renal effects and metabolism of these drugs in Fischer 344 rats, and animal model for inorganic fluoride nephrotoxicity; acute anesthetic and chronic subanesthetic exposure will be utilized. Renal function will be measured and pathological examination of kidney tissue accomplished with light and electron microscopy. Metabolite excretion will be measured and identification of specific compounds made, when possible. We also plan to study the effects of treatment with enzyme inducing drugs on the metabolism of fluorinated anesthetics and the development of anesthetic induced nephrotoxicity. In vitro studies will be carried out with hepatic microsome preparations in order to estimate kinetics of defluorination. Predictions of anesthetic stability will be made based on calculations of their molecular orbital bonding strength. The synthesis of in vivo, in vitro and theoretical data will allow us to formulate a concept of anesthetic nephrotoxicity so that the anesthesiologist can predict the risk of this complication in surgical patients.